Yukihiko Shirayama

Teikyo University, Edo, Tōkyō, Japan

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Publications (86)296.59 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Treatment-resistant depression is a challenging problem in the clinical setting. Tipepidine has been used as a non-narcotic antitussive in Japan since 1959. We administered tipepidine to 11 patients with treatment-resistant depression. Tipepidine was given for 8 weeks as an augmentation. Tipepidine significantly improved depression scores on the Hamilton Rating Scale for depression. Add-on treatment with tipepidine significantly improved scores on the trail making test and Rey auditory verbal learning test. However, no changes were observed in blood concentrations of stress-related hormones (adrenocorticotropic hormone, cortisol, dehydroepiandrosterone sulphate) with tipepidine augmentation. Tipepidine might be a potential therapeutic drug for treatment-resistant depression.
    Acta Neuropsychiatrica 07/2015; DOI:10.1017/neu.2015.43 · 0.64 Impact Factor
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    ABSTRACT: In humans, long-term antipsychotic treatment is known to induce movement disorders and a psychosis, called dopamine supersensitivity psychosis (DSP). The mechanism by which chronic administration of antipsychotic(s) causes DSP may be the treatment-induced up-regulation of dopamine D2 receptors (DRD2). G protein-coupled receptor kinase 6 (GRK6) and beta-arrestin 2 (ARRB2) play important roles in the trafficking of DRD2 by phosphorylation and internalization. We investigated the effects of chronic continuous treatment with mini-pump-administered haloperidol (HAL) on the sensitivity of Wistar rats to dopamine, as measured by the locomotor response to methamphetamine (MAP) and the density of striatal DRD2. Chronic continuous treatment with HAL resulted in significantly higher locomotor response to MAP and significantly higher striatal DRD2 density compared with those in rats administered vehicle (VEH). Enzyme-linked immunosorbent assays revealed that striatal ARRB2 in DSP model rats tended to decrease in comparison with that in the VEH group. In addition, the ratio of GRK6/ARRB2 in DSP model rats was significantly higher than that in controls. Our results suggest that alterations of the GRK6 and ARRB2 system could induce both DRD2 up-regulation and impairment of the dopamine signaling pathway, resulting potentially in the development of DSP. © The Author(s) 2015.
    Journal of Psychopharmacology 07/2015; DOI:10.1177/0269881115593903 · 2.81 Impact Factor
  • Chun Yang · Yukihiko Shirayama · Ji-Chun Zhang · Qian Ren · Kenji Hashimoto
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    ABSTRACT: Accumulating evidences suggest that pro-inflammatory cytokines such as interleukin-6 (IL-6) play a role in the pathophysiology of depression. In the learned helplessness (LH) paradigm, ~35% rats are resilient to inescapable stress. Levels of IL-6 in the serum and medial prefrontal cortex (mPFC) of LH rats (susceptible) and non-LH rats (resilience) were measured using enzyme-linked immunosorbent assay and western blot analysis, respectively. Serum levels of IL-6 in the LH rats were significantly higher than those of control and non-LH rats. In contrast, tissue levels of IL-6 in the mPFC were not different among three groups. The results suggest that peripheral IL-6 may contribute to resilience versus susceptibility to inescapable stress.
    Acta Neuropsychiatrica 05/2015; DOI:10.1017/neu.2015.36 · 0.64 Impact Factor
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    ABSTRACT: The role of neuropeptide S (NPS) in depression remains unclear. We examined the antidepressant-like effects of NPS infusions into the shell or core regions of the nucleus accumbens (NAc) and into the bed nucleus of the stria terminalis (BNST) of learned helplessness (LH) rats (an animal model of depression). Infusions of NPS (10 pmole/side) into the NAc shell, but not the NAc core and BNST, exerted antidepressant-like effects in the LH paradigm. Implying that behavioral deficits could be improved in the conditioned avoidance test. Coinfusion of SHA68 (an NPS receptor antagonist, 100 pmole/side) with NPS into the NAc shell blocked these effects. In contrast, NPS receptor antagonism by SHA68 in the BNST induced antidepressant-like effects. Infusions of NPS into the NAc shell or SHA68 into the BNST did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. These results suggest that excitatory and inhibitory actions by the NPS system are integral to the depression in LH animals. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 05/2015; 291. DOI:10.1016/j.bbr.2015.05.007 · 3.39 Impact Factor
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    ABSTRACT: Impairment on the Iowa Gambling Task has been reported in patients with schizophrenia, but the results are inconsistent.•Subjects were differentiated based on the whether they expressed certainty for advantageous strategy in the course of the task.•Patients with schizophrenia without certainty failed to show card choice shift from disadvantageous to advantageous decks.•Uncertainty for an advantageous strategy was related to SANS scores in schizophrenia.•Big penalties affected learning in controls, but not patients suffering from schizophrenia with or without certainty.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2015; 57. DOI:10.1016/j.pnpbp.2014.10.007 · 4.03 Impact Factor
  • Chun Yang · Yukihiko Shirayama · Ji-Chun Zhang · Qian Ren · Kenji Hashimoto
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    ABSTRACT: Background: In the learned helplessness (LH) paradigm, approximately 35% rats are resilient to inescapable stress. Methods: The roles of brain-derived neurotrophic factor (BDNF) and dendritic spine density in the brain regions of LH (susceptible) and non-LH rats (resilience) were examined. Results and Conclusions: BDNF levels in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) were significantly lower in the LH group than in the control and non-LH groups, whereas BDNF levels in the nucleus accumbens (NAc) in the LH group but not the non-LH group were significantly higher than those in the control group. Furthermore, spine density in the prelimbic cortex, CA3, and DG was significantly lower in the LH group than in the control and non-LH groups, although spine density in the NAc was significantly higher in the LH group than in the control and non-LH groups. The results suggest that regional differences in BDNF levels and spine density in rat brain may contribute to resilience to inescapable stress. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(7). DOI:10.1093/ijnp/pyu121 · 5.26 Impact Factor
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    ABSTRACT: Objective This open-label study examined the effects of ramelteon on cognitive functions in 10 outpatients with schizophrenia. Methods Ramelteon (8 mg/day) was administered to 10 patients with schizophrenia for six months. The verbal fluency test, Trail-Making Test, the Wisconsin Card Sorting Test, the Stroop Test, the Digit Span Distraction Test, Iowa Gambling Task, the Rey Auditory Verbal Learning Test were evaluated at baseline and 6 months after treatment with ramelteon. Results Ramelteon improved significantly the scores of Rey Auditory Verbal Learning Test. Additionally, ramelteon exerted improvements in the verbal fluency and Iowa Gambling Task in 4 patients. Conclusion Ramelteon could be a potential therapeutic drug, in adjunctive treatment of learning and memory deficits seen in patients with schizophrenia.
    Clinical Psychopharmacology and Neuroscience 12/2014; 12(3):2093-4327215. DOI:10.9758/cpn.2014.12.3.215
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    Ji-Chun Zhang · Jin Wu · Yuko Fujita · Wei Yao · Qian Ren · Chun Yang · Su-Xia Li · Yukihiko Shirayama · Kenji Hashimoto
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression. In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined. LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc. The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(4). DOI:10.1093/ijnp/pyu077 · 5.26 Impact Factor
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    ABSTRACT: The NEO Personality Inventory-Revised (NEO) and the Temperament and Character Inventory (TCI) were administered to patients with treatment-resistant depression (n=21) before lithium augmentation. Analysis showed that the poor outcome group (n=11) had lower openness scores on the NEO, and lower cooperativeness scores on the TCI compared with the good outcome group (n=10). These findings may be predictors of poor responsiveness to lithium augmentation in the treatment of antidepressant-resistant depression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research 10/2014; 220(3):1144-1146. DOI:10.1016/j.psychres.2014.09.023 · 2.68 Impact Factor
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    ABSTRACT: Background The psychological aspects of treatment-resistant and remitted depression are not well documented. Methods We administered the Minnesota Multiphasic Personality Inventory (MMPI) to patients with treatment-resistant depression (n = 34), remitted depression (n = 25), acute depression (n = 21), and healthy controls (n = 64). Pessimism and optimism were also evaluated by MMPI. Results ANOVA and post-hoc tests demonstrated that patients with treatment-resistant and acute depression showed similarly high scores for frequent scale (F), hypochondriasis, depression, conversion hysteria, psychopathic device, paranoia, psychasthenia and schizophrenia on the MMPI compared with normal controls. Patients with treatment-resistant depression, but not acute depression registered high on the scale for cannot say answer. Using Student's t-test, patients with remitted depression registered higher on depression and social introversion scales, compared with normal controls. For pessimism and optimism, patients with treatment-resistant depression demonstrated similar changes to acutely depressed patients. Remitted depression patients showed lower optimism than normal controls by Student's t-test, even though these patients were deemed recovered from depression using HAM-D. Conclusions The patients with remitted depression and treatment-resistant depression showed subtle alterations on the MMPI, which may explain the hidden psychological features in these cohorts.
    PLoS ONE 10/2014; 9(10):e109137. DOI:10.1371/journal.pone.0109137 · 3.23 Impact Factor
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    ABSTRACT: Several lines of evidence suggest that glial cell-line derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric and neurodegenerative disorders. In this study, we investigated the association between GDNF serum levels and the clinical status of medicated patients with schizophrenia. Sixty-three medicated patients with schizophrenia and 52 age- and sex-matched healthy controls were recruited. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Serum levels of GDNF were determined using an ELISA method. Serum levels of GDNF did not differ between schizophrenia patients and controls. Higher GDNF serum levels were associated with better performances on the Digit Span in healthy controls but not in schizophrenics. At the same time, higher GDNF serum levels were associated with severe attention deficits on the SANS subscale, in schizophrenics. Our preliminary study suggests that serum levels of GDNF may be an unsuitable biomarker for schizophrenia, although it may be associated with working memory in healthy controls and the pathophysiology of attention deficits in schizophrenia.
    Neuroscience Letters 05/2014; 575. DOI:10.1016/j.neulet.2014.05.034 · 2.06 Impact Factor
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    ABSTRACT: A meta-analysis study reported serum brain-derived neurotrophic factor (BDNF) levels as a potential biomarker for schizophrenia. However, at the time, commercially available human ELISA kits were unable to distinguish between pro-BDNF (precursor BDNF) and mature BDNF, because of limited antibody specificity. Here, we used new ELISA kits, to examine serum levels of mature BDNF and matrix metalloproteinase-9 (MMP-9), which converts pro-BDNF to mature BDNF in schizophrenia. Sixty-three patients with chronic schizophrenia and 52 age- and sex-matched healthy controls were enrolled. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Neither serum mature BDNF nor MMP-9 levels differed between patients and controls. In male subgroups, serum MMP-9 levels of smoking patients were higher than those of non-smoking patients, but this was not observed in male controls or the female subgroup. In patients, serum mature BDNF levels were associated with SANS total scores and the Information subtest scores of the Wechsler Adult Intelligence Scale Revised (WAIS-R), while serum MMP-9 levels were associated with smoking and category fluency scores. These findings suggest that neither mature BDNF nor MMP-9 is a suitable biomarker for schizophrenia, although further studies using large samples are needed.
    12/2013; 215(2). DOI:10.1016/j.psychres.2013.12.009
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    ABSTRACT: Recently, we reported that low reward dependence, and to a lesser extent, low cooperativeness in the Temperature and Character Inventory (TCI) may be risk factors for treatment-resistant depression. Here, we analyzed additional psychological traits in these patients. We administered Costa and McCrae's five-factor model personality inventory, NEO Personality Inventory-Revised (NEO-PI-R), to antidepressant-treatment resistant depressed patients (n = 35), remitted depressed patients (n = 27), and healthy controls (n = 66). We also evaluated the relationships between scores on NEO and TCI, using the same cohort of patients with treatment-resistant depression, as our previous study. Patients with treatment-resistant depression showed high scores for neuroticism, low scores for extraversion, openness and conscientiousness, without changes in agreeableness, on the NEO. However, patients in remitted depression showed no significant scores on NEO. Patients with treatment-resistant depression and low openness on NEO showed positive relationships with reward dependence and cooperativeness on the TCI. Many studies have reported that depressed patients show high neuroticism, low extraversion and low conscientiousness on the NEO. Our study highlights low openness on the NEO, as a risk mediator in treatment-resistant depression. This newly identified trait should be included as a risk factor in treatment-resistant depression.
    PLoS ONE 09/2013; 8(9):e71964. DOI:10.1371/journal.pone.0071964 · 3.23 Impact Factor
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    ABSTRACT: The clinical outcome of antidepressant treatment in patients with major depressive disorder (MDD) is thought to be associated with personality traits. A number of studies suggest that depressed patients show high harm avoidance, low self-directedness and cooperativeness, as measured on the Temperament and Character Inventory (TCI). However, the psychology of these patients is not well documented. Psychological evaluation using Cloninger's TCI, was performed on treatment-resistant MDD patients (n = 35), remission MDD patients (n = 31), and age- and gender-matched healthy controls (n = 174). Treatment-resistant patients demonstrated high scores for harm avoidance, and low scores for reward dependence, self-directedness, and cooperativeness using the TCI, compared with healthy controls and remission patients. Interestingly, patients in remission continued to show significantly high scores for harm avoidance, but not other traits in the TCI compared with controls. Moreover, there was a significant negative correlation between reward dependence and harm avoidance in the treatment-resistant depression cohort, which was absent in the control and remitted depression groups. This study suggests that low reward dependence and to a lesser extent, low cooperativeness in the TCI may be risk factors for treatment-resistant depression.
    PLoS ONE 05/2013; 8(5):e63756. DOI:10.1371/journal.pone.0063756 · 3.23 Impact Factor
  • Katsumasa Muneoka · Yukihiko Shirayama · Mao Horio · Masaomi Iyo · Kenji Hashimoto
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    ABSTRACT: RATIONALE: Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). OBJECTIVES: We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. METHODS: LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. RESULTS: The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. CONCLUSIONS: The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression.
    Psychopharmacology 04/2013; 229(1). DOI:10.1007/s00213-013-3080-2 · 3.99 Impact Factor
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    ABSTRACT: Cognitive impairments in schizophrenia are associated with suboptimal psychosocial performance. Several lines of evidence have suggested that endoplasmic reticulum protein sigma-1 receptors were involved in cognitive impairments in patients with schizophrenia and that the sigma-1 receptor agonist fluvoxamine was effective in treating cognitive impairments in animal models of schizophrenia and in some patients with schizophrenia. A randomized, double-blind, placebo-controlled, parallel trial of fluvoxamine adjunctive therapy in patients with schizophrenia was performed. A total of 48 patients with chronic schizophrenia were enrolled. Subjects were randomly assigned to an 8-week administration of add-on fluvoxamine (n = 24, titrated up to 150 mg/d) or placebo (n =24) in a total 12-week double-blind trial. The primary outcome measure was the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing visual memory, working memory, attention, and executive function. The secondary outcome measures were the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and the Montgomery-Åsberg Depression Rating Scale. Fluvoxamine was well tolerated. No significant time × group interaction effects were observed in the scores of the CANTAB, Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, or the Montgomery-Åsberg Depression Rating Scale. However, in secondary analyses, the change from baseline to end point on the Spatial Working Memory strategy score (executive function) of CANTAB improved in the fluvoxamine group. This study suggests no major benefit of fluvoxamine adjunctive therapy to improve cognitive impairments in patients with schizophrenia. Nevertheless, a further study using a large sample size will be needed to confirm the secondary analyses findings.
    Journal of clinical psychopharmacology 08/2012; 32(5):593-601. DOI:10.1097/JCP.0b013e3182664cfc · 3.76 Impact Factor
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    Hisahito Ishida · Masaaki Iwata · Yukihiko Shirayama · Katsumasa Muneoka
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    ABSTRACT: Background: Among neurotransmitter influencing memory formation, the noradrenergic system has been recognized as an important system. Memory formation involves various regions including the prefrontal cortex, hippocampus, amygdala and septum. Method: We investigated the effects of milnacipran on passive avoidance task and evaluated Fos counting in the prefrontal cortex, hippocampus, septum, amygdala and nucleus accumbens. Results: The milnacip-ran-treated rats (20 mg/kg, 4 days) showed a significant decrease in the number of Fos-immunoreactive cells in the in-fralimbic portion of prefrontal cortex, the shell portion of nucleus accumbens and the CA1 region of hippocampus, but a significant increase in the Fos counts in the lateral septum with no changes in the Fos counts in the striatum and amyg-dala. The milnacipran-treated rats showed amelioration in memory extinction (although not statistically significant), but not in memory acquisition and consolidation in the passive avoidance test. Conclusion: The differential activation of the brain regions might be possible sites for ameliorating memory extinction as well as antidepressant effects.
    Journal of Behavioral and Brain Science 01/2012; 02(02). DOI:10.4236/jbbs.2012.22016
  • Masatoshi Suzuki · Koichi Sato · Yukihiko Shirayama
    Nippon rinsho. Japanese journal of clinical medicine 12/2011; 69 Suppl 10(Pt 2):47-51.
  • Katsumasa Muneoka · Yukihiko Shirayama · Katsushi Kon · Masaharu Kawabe · Sho Kimura
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    ABSTRACT: A 68-year-old woman showed obsessive thought that she could not remember the names of people or items that she saw. She repeatedly asked her husband to recall names of unspecified people and checked the garbage to find the names of items. The patient had a history of cerebral infarctions in the left middle cerebral artery regions 2 and 15 months before the emergence of her symptoms. A magnetic resonance imaging examination showed signs of an old infarction in the left basal ganglia and ischemic signs in the right temporal lobe. Her obsessive-compulsive symptoms relating to words were successfully treated with a serotonin selective reuptake inhibitor, paroxetine, at the dose of 40 mg/d. Her scores on the Yale-Brown Obsessive Compulsive Scale reduced from 31 to 8 points after this treatment. This case may suggest therapeutic modulation of language-related cortical activity elicited by paroxetine.
    Clinical neuropharmacology 11/2011; 34(6):260-1. DOI:10.1097/WNF.0b013e3182329670 · 1.84 Impact Factor
  • Yukihiko Shirayama · Takeshi Konishi · Kenji Hashimoto
    Journal of clinical psychopharmacology 10/2011; 31(5):659-61. DOI:10.1097/JCP.0b013e31822c94fd · 3.76 Impact Factor

Publication Stats

3k Citations
296.59 Total Impact Points

Institutions

  • 2010–2015
    • Teikyo University
      Edo, Tōkyō, Japan
  • 2014
    • Peking University
      Peping, Beijing, China
  • 2008–2009
    • Chiba University
      • Department of Psychiatry
      Tiba, Chiba, Japan
  • 2004–2008
    • Tottori University
      • • Faculty of Medicine
      • • Department of Multidisciplinary Internal Medicine
      TTJ, Tottori, Japan
  • 1993–2004
    • National Center of Neurology and Psychiatry
      • • Department of Psychophysiology
      • • Department of Mental Disorder Research
      Кодаиры, Tōkyō, Japan
  • 2002
    • Showa University
      Shinagawa, Tōkyō, Japan
    • Kagoshima University
      • Department of Neuropsychiatry
      Kagosima, Kagoshima, Japan
  • 2000–2002
    • Yale University
      • Department of Psychiatry
      New Haven, Connecticut, United States